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A Novel Nanoconjugate of Landomycin A with C60 Fullerene for Cancer Targeted Therapy: In Vitro Studies

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Abstract

Introduction

Landomycins are a subgroup of angucycline antibiotics that are produced by Streptomyces bacteria and possess strong antineoplastic potential. Literature data suggest that enhancement of the therapeutic activity of this drug may be achieved by means of creating specific drug delivery systems. Here we propose to adopt C60 fullerene as flexible and stable nanocarrier for landomycin delivery into tumor cells.

Methods

The methods of molecular modelling, dynamic light scattering and Fourier transform infrared spectroscopy were used to study the assembly of C60 fullerene and the anticancer drug Landomycin A (LA) in aqueous solution. Cytotoxic activity of this nanocomplex was studied in vitro towards two cancer cell lines in comparison to human mesenchymal stem cells (hMSCs) using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) test and a live/dead assay. The morphology of the cells incubated with fullerene–drug nanoparticles and their uptake into target cells were studied by scanning electron microscopy and fluorescence light microscopy.

Results

The viability of primary cells (hMSCs, as a model for healthy cells) and cancer cell lines (human osteosarcoma cells, MG-63, and mouse mammary cells, 4T1, as models for cancer cells) was studied after incubation with water-soluble C60 fullerenes, LA and the mixture C60 + LA. The C60 + LA nanocomplex in contrast to LA alone showed higher toxicity towards cancer cells and lower toxicity towards normal cells, whereas the water-soluble C60 fullerenes at the same concentration were not toxic for the cells.

Conclusions

The obtained physico-chemical data indicate a complexation between the two compounds, leading to the formation of a C60 + LA nanocomposite. It was concluded that immobilization of LA on C60 fullerene enhances selectivity of action of this anticancer drug in vitro, indicating on possibility of further preclinical studies of novel C60 + LA nanocomposites on animal tumor models.

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Abbreviations

4T1:

Mouse mammary cells

C60FAS:

C60 fullerene aqueous solution

Cis:

Cisplatin

DAPI:

4′, 6 Diamidino 2 phenylindole

DLS:

Dynamic light scattering

DMEM:

Dulbecco’s modified eagle medium

DMSO:

Dimethyl sulfoxide

Dox:

Doxorubicin

EPR:

Enhanced permeability and retention

FCS:

Fetal calf serum

FTIR:

Fourier transform infrared spectroscopy

hMSCs:

Human mesenchymal stem cells

LA:

Landomycin A

MG-63:

Human osteosarcoma cells

MTT:

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide

PBS:

Phosphate-buffered saline

PDI :

Polydispersity index

SEM:

Scanning electron microscopy

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Acknowledgments

V. Bilobrov is grateful to DAAD for financial support within the framework of the Leonhard-Euler Program. This work was partially supported by STCU Project N6256 and state support to Leading Research Group 5889.2018.3.

Conflict of interest

V. Bilobrov, V. Sokolova, S. Prylutska, R. Panchuk, O. Litsis, V. Osetskyi, M. Evstigneev, Yu. Prylutskyy, M. Epple, U. Ritter, J. Rohr declare that they have no conflicts of interest.

Ethical Approval

Neither human studies, nor animal studies were carried out by the authors for this article.

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Authors and Affiliations

  1. Taras Shevchenko National University of Kyiv, Volodymyrska Str. 64, Kyiv, 01601, Ukraine

    V. Bilobrov, S. Prylutska, O. Litsis, V. Osetskyi & Yu. Prylutskyy

  2. Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, Universitaetsstr. 5-7, 45117, Essen, Germany

    V. Sokolova & M. Epple

  3. Institute of Cell Biology, National Academy of Sciences of Ukraine, Drahomanov Str. 14/16, L’viv, 79005, Ukraine

    R. Panchuk

  4. Department of Physics, Sevastopol State University, Universitetskaya str. 33, Sevastopol, 299053, Crimea

    M. Evstigneev

  5. Institute of Chemistry and Biotechnology, Technical University of Ilmenau, Weimarer Str. 25, 98693, Ilmenau, Germany

    U. Ritter

  6. College of Pharmacy, University of Kentucky, South Limestone Str. 789, Lexington, 40536-0596, USA

    J. Rohr

Authors
  1. V. Bilobrov
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  2. V. Sokolova
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  3. S. Prylutska
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  4. R. Panchuk
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  5. O. Litsis
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  6. V. Osetskyi
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  7. M. Evstigneev
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  8. Yu. Prylutskyy
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  9. M. Epple
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  10. U. Ritter
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  11. J. Rohr
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Contributions

The work presented here was carried out in collaboration between all the authors. RP, JR, VO and YP created and characterized nanomaterials. VB and VS performed in vitro and fluorescence microscopy studies. OL and SP characterized nanomaterials using FTIR analysis. ME performed the computer simulations. UR synthesized and characterized C60FAS. M. Epple and YP coordinated the experimental work, analyzed the data, performed the statistical analysis, and wrote the manuscript. All authors discussed the results and commented on the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to M. Evstigneev or Yu. Prylutskyy.

Additional information

Associate Editor Michael R. King oversaw the review of this article.

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Bilobrov, V., Sokolova, V., Prylutska, S. et al. A Novel Nanoconjugate of Landomycin A with C60 Fullerene for Cancer Targeted Therapy: In Vitro Studies. Cel. Mol. Bioeng. 12, 41–51 (2019). https://doi.org/10.1007/s12195-018-0548-5

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